It is the intent of all sustained-release pharmaceutical preparations to provide a longer period of pharmacologic effect after the administration of a drug than is ordinarily experienced after the administration of immediate release preparations of the same drug. Such longer periods of efficacy can provide many inherent therapeutic benefits that are not achieved with corresponding immediate release preparations.
Another approach to sustained delivery of a therapeutically active agent is transdermal delivery systems, such as transdermal patches. Generally, transdermal patches contain a therapeutically active agent, a reservoir or matrix containing the active ingredient(s) and an adhesive which allows the transdermal device to adhere to the skin, allowing for the passage of the active agent from the device through the skin of the patient. Once the active agent has penetrated the skin layer, the drug is absorbed into the blood stream where it can exert a desired pharmacotherapeutic effect.
In spite of the known art related to transdermal therapy, there exists a need for the transdermal delivery of a beneficial agent for the treatment of benign prostatic hypertrophy.
Terazosin, commercially available as Hytrin® in the U.S. from Abbott Laboratories (North Chicago, Ill. 60064, U.S.A.), is an alpha-1-selective adrenoceptor blocking agent used in the management of mild to moderate hypertension, as well as for benign prostatic hypertrophy. Terazosin relaxes the smooth muscle of the bladder neck, thus reducing bladder outlet obstruction. The dose for benign prostatic hypertrophy is (initially) 1 mg at bedtime, increasing as needed. Most patients require 10 mg per day, and some require an increase of the dosage to 20 mg per day.
Benign Prostatic Hyperplasia (BPH) pertains to nodular hyperplasia of a gland (adenomatous). Benign adenomatous hyperplasia of the periurethral prostate gland is commonly seen in men over the age of 50, causing variable degrees of bladder outlet obstruction. The etiology is unknown but may involve alterations in hormonal balance associated with aging.
Multiple fibroadenomatous nodules occur in the area around the urethra (periurethral region) of the prostate gland, probably originating within the periurethral glands themselves. The abnormal multiplication or increase in the number of normal cells in a normal arrangement in the tissue (hyperplasia), may involve the lateral walls of the prostate or may include tissue at the inferior margin of the vesical neck. As the lumen of the prostatic urethra is compromised, the outflow of urine is progressively obstructed. Incomplete bladder emptying causes stasis and predisposes to infection with secondary inflammatory changes in the bladder and upper urinary tract. Prolonged obstruction, even though incomplete, can compromise renal function. Urinary stasis also predisposes to calculus formation.
Symptoms of bladder outlet obstruction include progressive urinary frequency, urgency, and nocturia due to incomplete emptying and rapid refilling of the bladder. On rectal examination the prostate usually is enlarged, however, the size can be misleading. A prostate that is small by rectal examination may be sufficiently enlarged to cause obstruction. Congestion of superficial veins of the prostatic urethra can cause hematuria (bloody urine) secondary to rupture.
Symptoms of BPH are improved by treatment with alpha-1-adrenoceptors, which are abundant in the prostate, prostatic capsule and bladder neck. Alpha-1-adrenoceptors such as terazosin (The Merck Index, 11th Edition, Merck & Co., Inc., Rahway, N.J. U.S.A. 1989, hereby incorporated by reference) act by blocking adrenergic nerve activity of the smooth muscle. Because there are relatively few alpha-1-adrenoceptors in the bladder body, terazosin is able to reduce the bladder outlet obstruction without affecting bladder contractility.
Following oral administration, terazosin is almost completely absorbed, with minimal first-pass effect. Food may delay the time to peak concentrations by about 1 hour, but the presence of food has no significant effect on terazosin bioavailability. Antihypertensive effects are seen within 15 minutes, and peak plasma levels are observed approximately 1 hour after administration. The mean peak plasma concentrations of terazosin after a single dose of 0.1 to 10 mg has been reported to increase linearly (r=0.99) with increasing dose; the peak plasma concentration was from about 5 to about 12 μg/L. The plasma half-life is about 12 hours. In treatments from 1 to 5 days, the plasma drug concentrations increased proportionately with dosages up to 40 mg. Terazosin is extensively bound to plasma proteins (90-94%) and is metabolized by the liver to one active and three inactive metabolites. Excretion of terazosin occurs as both unchanged drug and metabolites in the urine (40%/o) and in the feces (60%). Only 10% of the terazosin dose is excreted renally as unchanged drug. Impaired renal function has no significant effect on the elimination of terazosin. Terazosin is minimally (10%) removed during hemodialysis.
The most common adverse effects of terazosin therapy are lightheadedness; dizziness (19%); headache (16%); drowsiness (5%); asthenia (weakness, tiredness, and fatigue) (11%); lethargy; nausea/vomiting (4.4%); peripheral edema (6%); nasal congestion (6%); and palpitations. Terazosin therapy can cause other adverse effects including rash, pruritus, urinary frequency, incontinence, blurred vision, xerostomia (dry mouth), vomiting, constipation, diarrhea, liver-function test abnormalities, diaphoresis, dyspnea, fever, and arthralgia.
Despite advances in the art, there remains a need for methods of treating patients with an agent for treating benign prostatic hypertrophy that provide effective levels of terazosin for prolonged periods of time while eliminating or minimizing asthenia, postural hypotension, dizziness, somnolence, nasal congestion and impotence side effects, thus providing a safe and effective method of management of benign prostatic hypertrophy.